Abstract
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that mediate the adaptive response of mammalian cells and tissues to changes in tissue oxygenation. In the present study, we show an age-dependent decline in cortical HIF-1alpha accumulation and activation of HIF target genes in response to hypoxia. This inducible response is significantly attenuated in the cerebral cortex of 18-mo-old Fischer 344 rat yet virtually absent in the cerebral cortex of 24-mo-old Fischer 344 rat. This attenuated HIF-1alpha response had no effect on mRNA upregulation of HIF-independent genes in the aged cortex. We have provided evidence that this absent HIF-1alpha response is directly correlated with an increase in the expression of the HIF regulatory enzyme, prolyl 4-hydroxylase (PHD). In addition, our study shows that cortical HIF-2alpha expression in senescent normoxic controls is also significantly greater than that of younger normoxic controls, despite no difference in HIF-2alpha mRNA levels. The posttranslational regulation of HIF-2alpha under normoxic conditions seems to be attenuated in the aged rat brain, which is an in vivo demonstration of differential regulation of HIF-1alpha and HIF-2alpha.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Age Factors
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Aging / genetics
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Aging / metabolism*
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Carbonic Anhydrase IX
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Carbonic Anhydrases / metabolism
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Cerebral Cortex / enzymology*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Enzymologic
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Glucose Transporter Type 1 / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Immediate-Early Proteins / metabolism
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Male
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism*
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Protein Processing, Post-Translational
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RNA, Messenger / metabolism
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Rats
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Rats, Inbred F344
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Up-Regulation
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Glucose Transporter Type 1
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immediate-Early Proteins
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RNA, Messenger
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Slc2a1 protein, rat
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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endothelial PAS domain-containing protein 1
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Procollagen-Proline Dioxygenase
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Egln1 protein, rat
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Egln3 protein, rat
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Ca9 protein, rat
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Carbonic Anhydrase IX
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Carbonic Anhydrases